Michael Scholz

Quantification of the Relative Biological Effectiveness for Ion Beam Radiotherapy: Direct Experimental Comparison of Proton and Carbon Ion Beams and a Novel Approach for Treatment Planning

PURPOSEnTo present the first direct experimental in vitro comparison of the biological effectiveness of range-equivalent protons and carbon ion beams for Chinese hamster ovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model.nnnMETHODS AND MATERIALSnCell survival was measured in the phantom after irradiation with two opposing fields, thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation.nnnRESULTSnThe experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions.nnnCONCLUSIONnBoth the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy.

Impact of enhancements in the local effect model (LEM) on the predicted RBE-weighted target dose distribution in carbon ion therapy.

Biological optimization for treatment planning in carbon ion therapy is currently based on the first version of the local effect model (LEM I). Further developments implemented in the latest version (LEM IV) allowed to predict more accurately the Relative Biological Effectiveness (RBE) in-vitro. The main goal of this study is to compare the LEM IV against LEM I under treatment-like conditions for idealized target geometries. Therefore, physical dose distributions resulting from the biological optimization with LEM I were used to recalculate the RBE-weighted dose distribution based on LEM IV. Input parameters representing the clinical endpoints late toxicity in the central nervous system and the tumor control for chordoma were chosen to investigate the impact of changes on the predicted isoeffective dose levels. The recalculated RBE-weighted dose distributions show an increase within the target region, and the mean RBE-weighted dose values are dependent on the geometry and decrease with increasing target dimension. The differences between predictions of LEM IV and LEM I are less than 10% for typical tumor volumes treated in the pilot project at GSI. Median RBE-weighted doses predicted by LEMxa0IV in the target region are consistent with clinically observed dose-response behavior as demonstrated by comparison to the 5-year local control curve for skull base chordoma.

Relative biological effectiveness of carbon ions for local tumor control of a radioresistant prostate carcinoma in the rat

PURPOSEnTo study the relative biological effectiveness (RBE) of carbon ion beams relative to X-rays for local tumor control in a syngeneic rat prostate tumor (Dunning subline R3327-AT1).nnnMETHODS AND MATERIALSnA total of 198 animals with tumors in the distal thigh were treated with increasing single and split doses of either (12)C ions or photons using a 20-mm spread-out Bragg peak. Endpoints of the study were local control (no tumor recurrence within 300 days) and volumetric changes after irradiation. The resulting values for D(50) (dose at 50% tumor control probability) were used to determine RBE values.nnnRESULTSnThe D(50) values for single doses were 32.9 ± 0.9 Gy for (12)C ions and 75.7 ± 1.6 Gy for photons. The respective values for split doses were 38.0 ± 2.3 Gy and 90.6 ± 2.3 Gy. The corresponding RBE values were 2.30 ± 0.08 for single and 2.38 ± 0.16 for split doses. The most prominent side effects were dry and moist desquamation of the skin, which disappeared within weeks.nnnCONCLUSIONnThe study confirmed the effectiveness of carbon ion therapy for severely radioresistant tumors. For 1- and 2-fraction photon and (12)C ion radiation, we have established individual D(50) values for local tumor control as well as related RBE values.

Temporal Lobe Reactions After Radiotherapy With Carbon Ions: Incidence and Estimation of the Relative Biological Effectiveness by the Local Effect Model

PURPOSEnTo identify predictors for the development of temporal lobe reactions (TLR) after carbon ion radiation therapy (RT) for radiation-resistant tumors in the central nervous system and to evaluate the predictions of the local effect model (LEM) used for calculation of the biologically effective dose.nnnMETHODS AND MATERIALSnThis retrospective study reports the TLR rates in patients with skull base chordomas and chondrosarcomas irradiated with carbon ions at GSI, Darmstadt, Germany, in the years 2002 and 2003. Calculation of the relative biological effectiveness and dose optimization of treatment plans were performed on the basis of the LEM. Clinical examinations and magnetic resonance imaging (MRI) were performed at 3, 6, and 12 months after RT and annually thereafter. Local contrast medium enhancement in temporal lobes, as detected on MRI, was regarded as radiation-induced TLR. Dose-volume histograms of 118 temporal lobes in 59 patients were analyzed, and 16 therapy-associated and 2 patient-associated factors were statistically evaluated for their predictive value for the occurrence of TLR.nnnRESULTSnMedian follow-up was 2.5 years (range, 0.3-6.6 years). Age and maximum dose applied to at least 1 cm(3) of the temporal lobe (D(max,V - 1 cm)3, maximum dose in the remaining temporal lobe volume, excluding the volume 1 cm(3) with the highest dose) were found to be the most important predictors for TLR. Dose response curves of D(max,V - 1 cm)3 were calculated. The biologically equivalent tolerance doses for the 5% and 50% probabilities to develop TLR were 68.8 ± 3.3 Gy equivalents (GyE) and 87.3 ± 2.8 GyE, respectively.nnnCONCLUSIONSnD(max,V - 1 cm)3 is predictive for radiation-induced TLR. The tolerance doses obtained seem to be consistent with published data for highly conformal photon and proton irradiations. We could not detect any clinically relevant deviations between clinical findings and expectations based on predictions of the LEM.

Design of and technical challenges involved in a framework for multicentric radiotherapy treatment planning studies

This report introduces a framework for comparing radiotherapy treatment planning in multicentric in silico clinical trials. Quality assurance, data incompatibility, transfer and storage issues, and uniform analysis of results are discussed. The solutions that are given provide a useful guide for the set-up of future multicentric planning studies or public repositories of high quality data.

Carbon ion irradiation of the rat spinal cord: Dependence of the relative biological effectiveness on linear energy transfer

PURPOSEnTo measure the relative biological effectiveness (RBE) of carbon ions in the rat spinal cord as a function of linear energy transfer (LET).nnnMETHODS AND MATERIALSnAs an extension of a previous study, the cervical spinal cord of rats was irradiated with single doses of carbon ions at 6 positions of a 6-cm spread-out Bragg peak (16-99 keV/μm). The TD50 values (dose at 50% complication probability) were determined according to dose-response curves for the development of paresis grade 2 within an observation time of 300 days. The RBEs were calculated using TD50 for photons of our previous study.nnnRESULTSnMinimum latency time was found to be dose-dependent, but not significantly LET-dependent. The TD50 values for the onset of paresis grade 2 within 300 days were 19.5 ± 0.4 Gy (16 keV/μm), 18.4 ± 0.4 Gy (21 keV/μm), 17.7 ± 0.3 Gy (36 keV/μm), 16.1 ± 1.2 Gy (45 keV/μm), 14.6 ± 0.5 Gy (66 keV/μm), and 14.8 ± 0.5 Gy (99 keV/μm). The corresponding RBEs increased from 1.26 ± 0.05 (16 keV/μm) up to 1.68 ± 0.08 at 66 keV/μm. Unexpectedly, the RBE at 99 keV/μm was comparable to that at 66 keV/μm.nnnCONCLUSIONSnThe data suggest a linear relation between RBE and LET at high doses for late effects in the spinal cord. Together with additional data from ongoing fractionated irradiation experiments, these data will provide an extended database to systematically benchmark RBE models for further improvements of carbon ion treatment planning.

Relative Biological Effectiveness of Carbon Ions in a Rat Prostate Carcinoma In Vivo: Comparison of 1, 2, and 6 Fractions

PURPOSEnTo determine the relative biological effectiveness (RBE) and the effective α/β ratio for local tumor control of a radioresistant rat prostate tumor (Dunning subline R3327-AT1) after 6 fractions of carbon ions and photons.nnnMETHODS AND MATERIALSnA total of 82 animals with tumors in the distal thigh were treated with 6 fractions of either photons or carbon ions, by use of increasing dose levels and a 2-cm spread-out Bragg peak. Endpoints of the study were local control (no tumor recurrence within 300 days) and volumetric changes after irradiation. The resulting values for dose at 50% tumor control probability were used to determine RBE values. Including data for 1 and 2 fractions from a previous study, we estimated α/β ratios.nnnRESULTSnFor 6 fractions, the values for dose at 50% tumor control probability were 116.6 ± 3.0 Gy for photons and 43.7 ± 2.3 Gy for carbon ions and the resulting RBE was 2.67 ± 0.15. The α/β ratio was 84.7 ± 13.8 Gy for photons and 66.0 ± 21.0 Gy for carbon ions. Using these data together with the linear-quadratic model, we estimated the maximum RBE to be 2.88 ± 0.27.nnnCONCLUSIONSnThe study confirmed the increased effectiveness of carbon ions relative to photons over the whole dose range for a highly radioresistant tumor. The maximum RBE below 3 is in line with other published inxa0vivo data. The RBE values may be used to benchmark RBE models. Hypoxia seems to have a major impact on the radiation response, although this still has to be confirmed by dedicated experiments.

Split dose carbon ion irradiation of the rat spinal cord: Dependence of the relative biological effectiveness on dose and linear energy transfer

PURPOSEnTo measure the relative biological effectiveness (RBE) of carbon ions relative to 15 MeV photons in the rat spinal cord for different linear energy transfers (LET) to validate model calculations.nnnMETHODS AND MATERIALSnThe cervical spinal cord of rats was irradiated with 2 fractions of carbon ions at six positions of a 6 cm spread-out Bragg-peak (SOBP, 16-99 keV/μm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Using previously published TD50-values for photons (Karger et al., 2006; Debus et al., 2003), RBE-values were determined and compared with predictions of two versions of the local effect model (LEM I and IV).nnnRESULTSnTD50-values for paresis grade II were 26.7 ± 0.4 Gy (16 keV/μm), 24.0 ± 0.3 Gy (21 keV/μm), 22.5 ± 0.3 Gy (36 keV/μm), 20.1 ± 1.2 Gy (45 keV/μm), 17.7 ± 0.3 Gy (66 keV/μm), and 14.9 ± 0.3 Gy (99 keV/μm). RBE-values increased from 1.28 ± 0.03 (16 keV/μm) up to 2.30 ± 0.06 at 99 keV/μm. At the applied high fractional doses, LEM I fits best at 16 keV/μm and deviates progressively toward higher LETs while LEM IV agrees best at 99 keV/μm and shows increasing deviations, especially below 66 keV/μm.nnnCONCLUSIONSnThe measured data improve the knowledge on the accuracy of RBE-calculations for carbon ions.

Chromosome fragmentation after irradiation with C ions

The premature chromosome condensation (PCC) technique has been used to compare chromatin breakage and repair in non-cycling CHO-K1 cells following high LET (C ions) and low LET (X-rays) irradiation. For both radiation qualities the average initial number of excess PCC fragments increases linearly with dose. However, the frequency of chromatin breaks follows the pattern of energy deposition and at higher LET values reveals clustering due to the large number of ionizing events being concentrated in a small volume of the cell nucleus. In consequence, the distribution of PCC chromosomes plus excess fragments among cells has followed Poisson statistics after X-ray irradiation while the overdispersion of the frequencies has been observed after C-irradiation indicating that a single particle traversal through a cell nucleus can produce multiple chromatin lesions.

The relative biological effectiveness of carbon ion irradiations of the rat spinal cord increases linearly with LET up to 99 keV/μm

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